This invention relates to certain 2-substituted-N-hydroxy-N-alkylcinnamamides, compositions containing those compounds and methods of their use.
The enzyme 5-lipoxygenase (5-LO) catalyzes the first step of a biochemical synthesis pathway by which arachidonic acid is converted into leukotrienes. Numerous and extremely potent biological activities have been associated with leukotrienes. Leukotrienes have been implicated as important mediators in a variety of disease states such as asthma, arthritis, psoriasis and allergy.
Considerable efforts have been directed toward the control of leukotrienes by means of leukotriene antagonists or by control of leukotriene biosynthesis. Generally, research efforts directed toward the control of leukotriene biosynthesis have been directed toward the discovery of inhibitors of the 5-LO pathway and, in particular, 5-LO specific inhibitors.
The principle focus of 5-LO inhibitor research efforts have been directed toward hydroxamic acid derivatives. Hydroxamic acid containing molecules rank among the most potent known in vitro inhibitors of 5-LO.
In U.K. Patent Application GB 2,196,629 certain ring substituted-N-hydroxy-N-substituted benzamide and cinnamamide compounds are disclosed as antileukotriene agents. The ring substituent may be a group having the Formula (Ra)(Rb) C.dbd.CH-- where (Ra)(Rb)C.dbd. is an unsaturated aliphatic hydrocarbylene group containing 3 to 19 carbon atoms; a group having the Formula R.sub.3 --C.tbd.C-- where R.sub.3 is a hydrogen atom or a saturated or unsaturated aliphatic hydrocarbyl group containing 1 to 18 carbon atoms; or a group having the Formula R.sub.4 --S-- where R.sub.4 is an aliphatic hydrocarbyl group containing 1 to 20 carbon atoms. The N-substituent may be a C.sub.1 -C.sub.6 alkyl group, a C.sub.3 -C.sub.7 cycloalkyl group or a substituted or unsubstituted aryl group.
In European Patent Application 0196184 certain aryl compounds are disclosed which include, among many others, certain cinnamohydroxamic acid analogs.
Neither of the above two references contain any recognition of the importance of a 2-position substituent on a cinnamohydroxamic acid skeleton.
Unfortunately, many of the known compounds suffer from toxicity problems, lack of bioavailability or are short lived in vivo. The hydroxamic acid group is rapidly metabolized to the corresponding, and inactive, carboxylic acid, particularly after oral administration. It was surprisingly discovered that the compounds of the present invention, as defined herein, are particularly advantageous inhibitors of 5-LO and have useful medical prophylactic and therapeutic properties. The compounds of the present invention and their pharmaceutically acceptable salts possess surprisingly high potency.
The compounds of the present invention differ from known compounds primarily by the requirement for an alkenyl bridge between the phenyl ring and the hydroxamic acid group as well as the requirement for a 2-position substituent on the phenyl ring. The unexpected and surprising advantages of the compounds of the present invention are believed at least in part to be a consequence of the alkenyl bridge and/or the type and position of substituents on the phenyl ring.
Accordingly, it is a primary object of the present invention to provide novel 2-substituted-N-hydroxy-N-alkyl cinnamamides which are potent selective 5-LO inhibitors and useful in the treatment of asthma and allergic diseases, inflammatory bowel disease, psoriasis, shock, adult respiratory distress syndrome (ARDS) and arthritis.
A further object of the present invention is to provide therapeutic compositions for treating said diseases and disorders.
Still another object is to provide methods for treating said diseases and disorders.
Other objects, features and advantages will become apparent to those skilled in the art from the following description and claims.